Antifungal composition



United States Patent ANTIFUNGAL COMPOSITION Laszlo Reiner, Essex Fells,N. 1., assignor to Wallace & Tiernan Company, Inc., a corporation of NewJersey No Drawing. Application September 6, 1951, Serial No. 245,431

6 Claims. (Cl. 167-58) For antifungal purposes, i. e. to prevent orinhibit mold growth, both in non-therapeutic circumstances and in theprevention or treatment of fungus infections, salicylanilide has hadconsiderable use. Although some chloro deriva tives of salicylanilidehave been known, and although such derivatives of the compound might beexpected to exhibit antifungal properties, it does not appear that anyone of them has received extensive use for the purpose. The absence ofacceptance of the chloro derivatives as antifungal agents is presumablyoccasioned by the fact (confirmed by the investigations reported below)that each of these derivatives of salicylanilide appears to be quitespecific in its action against various fungi. That is to say, thesederivatives have been found to be relatively inactive against a numberof fungi, which are usually considered resistant, whereas thederivatives will inhibit the growth of other fungi, even at relativelylow concentrations of the agent, such other fungi being deemed to becharacterized by low resistance to agents of this sort. In other words,the selective action of the chloro derivatives of salicylanilide hasimposed a serious limitation on the utility of such compounds forinhibiting or preventing growth of mold organisms, so that there hasapparently been no practical use of them.

In arriving at the discovery upon which the present invention ispredicated, and at the same time in taking account of the above facts,the following hypothesis was conceived, namely that the apparentlyselective action of various chloro derivatives of salicylanilide is notdue, or at least is not solely due, to any inherent specificity in thecompounds with respect to their antifungal action on various organisms,but is, in some manner, determined by certain physico-chemicalcharacteristics of the compounds, or more particularly by specialfactors such as theirlow solubility, e. g. in water or other aqueousmedia in which they are called upon to function. That is to say, it isnow conceived that the chloro derivatives of salicylanilide may actuallyhave a high intrinsic activity toward any one of the organisms inquestion, but because of one or more factors such as just mentioned, thecompounds cannot effectively exert their action toward certain organismsor under certain conditions. Itwill be understood that the termintrinsic activity is used to mean the activity which a compoundexhibits or which it can be expected to exhibit at a certainconcentration, irrespective of whether or not this concentration can berealized under the given condition of the test. As a furtherillustration of this concept and as an illustration of the procedure bywhich the value of the intrinsic activity can be experimentallyapproximated by extrapolation: supposing that a compound is. capable ofkilling 1% of the population of a particular micro-organism, one candetermine by extrapolation, using some of the known functionalrelationships between the death rate of micro-organisms andconcentration, the concentration which would be needed to kill 50% ofthe same population under the same conditions even though theconcentration thus determined with approximation cannot be realizedbecause of the low solubility of the compound in question. Furthermore,even if the value of the intrinsic activity cannot be determined itsexistence can be postulated.

The present invention, as more fully explained below, is believed tomake it possible to utilize the high intrinsic activity of chlorinatedsalicylanilide derivatives; in any event, whether the above hypothesisandthe assumption of the existence of high intrinsic activity arecorrect or not, the discovery of the present invention has yieldedcompositions of marked effectiveness and utility for the prevention offungus growth, and particularly in the case of so-called resistantorganisms, where these compounds have not heretofore been deemedsatisfactory agents.

In general, the chlorinated salicylanilides with which the presentinvention is concerned are the following: salicylanilide derivatives inwhich the ring of the salicylic acid moiety of the molecule issubstituted by a chlorine atom in the 5-position or in the 3-position,or by chlorine atoms in both positions, although derivatives in whichonly the 5-position is chlorinated appear now to be of specialsuperiority (in the invention) and are therefore preferred;salicylanilide derivatives in which the ring of the aniline moiety ofthe molecule is substituted by one or more chlorine atoms in the ortho-,paraand metapositions; and finally, salicylanilide derivatives in whichboth rings are chlorinated, each in one or more of the positionsmentioned. Thus in a generic sense, the chloro derivatives to which theinvention relates are those which involve one or more chlorine atomssubstituted in either or both of the rings respectively of thesalicyclic acid and aniline moieties, although as will appear below,certain specific chloro derivatives or classes of same are believed tobe specially advantageous in the antifungal compositions. By way ofexample of chloro derivatives to which the invention relates, mention ismade of the following, notably useful and more or less readilyproducible compounds; anilides derived from salicyclic acid and4-chloroaniline, 3-chloroaniline, 2-chloroaniline, 2,4-dichloroaniline,3,4-dichloroaniline, 3,5-dichloroaniline, and 2,4,6- trichloroaniline;3-chlorosalicylanilide, S-chlorosalicylanilide, and5,3-dichlorosalicylanilide; 5, 4-dichlorosalicylanilide,5,3-dichlorosalicylanilide, 5,2'-dichlorosalicylanilide,5,2',4'-trichlorosalicylanilide, 5,3,4-trichlorosalicylanilide,5,3',5-trichlorosalicylanilide, and 5,2',4,6- tetrachlorosalicylanilide.

Investigation has further revealed that the chloro derivatives ofsalicylanilide not only exhibit the apparent specificity mentionedabove, but also seem to have activity which varies with conditions in adifferent manner, respectively for different organisms. For instance,against the organism T richophyton interdigitale all of the chlorinatedcompounds show a growth preventing action in lower concentration thanthe unsubstituted salicylanilide, such action being influenced in aparticular way by the hydrogen ion concentration. Thus Within theover-all range of pH values at which the organism grows well, theactivity of the chloro derivatives is observed to be less at higher pHvalues (i. e. smaller hydrogen ion concentrations) than at lower values.As the same time none of these chloro compounds has been found to showactivity of practically useful character, at any attainableconcentration, against certain organisms such as Momlia albicans orSaccharomyces cerevisiae. Even with respect, however, tosuch activity asmay be detected, a different relation to pH is noted. For example, ifthe pH of the medium is increased (i. e., the hydrogen ion concentrationreduced), an increase has been observed in the slight activity whicheach of the chloro derivatives exhibits toward Saccharomyces cerevisiae.

Thus these compounds behave, qualitatively, in a different way towarddifferent mold organisms, such as T. interdigilale on the one hand andS. cerevisiae on the other. The apparent contradiction may now beexplained, however, in a manner substantiating the hypothesis mentionedabove. That is to say, the chloro derivativesappear to have a greatersolubility at highr' pH values, indeed such that a concentration of eachindividual compound can be reached which may even be high enough toinhibit the growth of Saccharomyces cerevisiae; yet at the higher pHvalues the intrinsic activity of the compound, e. g. as observed againstTrichophyton interdigitale (for which the effective concentrations arelow and well within the limits of solubility of the com- It mighttherefore seem that this phenomenon could be put to actual antifungaluse, as by employing a selected chloro-derivative of salicylanilide in amedium providing a high pH, the concept being that the compound wouldthen be sufliciently soluble (i. e. in the aqueous medium) as to attaina dissolved concentration where it would be effective against theorganisms toward which it has heretofore been deemed inactive. Underpractical conditions, however, attainment of a sufficiently high pH isoften not possible; even if the difficulty in that respect wereovercome, there remains a serious potential disadvantage in that acomposition having a very high pH may be harmful to fabrics, leather,living skin or tissues, hair and similar materials upon which antifungaltreatment is desired.

To the end of avoiding such difficulties while providing improvedantifungal agents having new and special advantages in a variety ofrespects, the present invention embraces the discovery that compositionscomprising the combination of two or more compounds selected from theclass that consists of the chlorosalicylanilides and unsubstitutedsalicylanilide, will prevent growth of even the most resistant funguswhich cannot be effectively inhibited in growth by any amount of thechloro derivatives when used singly and which is sensitive tounsubstituted salicylanilide by itself only when used in much higherconcentrations, i. e. greater than the total concentration of thecombination of these compounds in the new composition. Preferably atleast two chlorosalicyl anilides are included; indeed especiallysatisfactory results, representing a notable, specific improvement, are

achieved where the composition embraces several substances of the statedclass, for instance at least three of the chloro derivatives, or thecombination of the unsubstituted compound with at least two of thechloro compounds. Thus combined in suitable proportions, the ingredientsof the composition appear to coact in accordance with the hypothesesexplained above, e. g. in that whereas each chloro derivative may bepresent only in no more than the low concentration attainable at aconvenient pH, the combined effect is equal to the theoretical, highintrinsic activity which each derivative might achieve but for thepractical limitations on its reaching an appropriately largeconcentration.

In any event, and whether or not these theoretical considerationsrepresent a true explanation of the phenomena, the unusual results andadvantages achieved by the described compositions have been abundantlydem onstrated by actual test. For example, in one series of experimentsthe growth inhibiting action of salicylam'lide and various chloroderivatives of salicylanflide toward a resistant organism were tested,and by comparison test was made of the action of combinations of suchcompounds, i. e. in accordance with the present invention. The testorganism was saccharomyces cerevisiae, and the medium was Sabouraudsbroth containing 1% ethanol, the tests being performed at a pH of 6.3.The following 5 table sets forth the successive tests and resultsobtained,

including the quantities of salicylanilide or its chloroderivativeemployed in each case:

TABLE I n a I Amount used (mg/100 cc.) of Salzcylamlzde or it derivativeUnsubsti- 5,4- 5,2'- 5,4',2' 5 tuted 5-Chloro' dichloro dichlorotrichloro Result No growth. Growth.

Do. Do. Do. Do. No growth significance (since .even when larger amountsof each substance were introduced, no antifungal activity was noticed),except to show that an amount of each substance generally e'qual to orgreater than the total concentration in the combined composition, wasineffective to inhibit propagation of the organism.

Thus from the foregoing table, it appears that no concentration of anyone of these chloro compounds was found which would prevent mold growthwhen used alone. However, when the four compounds are simultaneouslypresent, each in a concentration which is not more than one-quarter ofthe concentration which fails (by itself) to influence growth, thecombination will prevent mold growth completely. Furthermore, if aslittle as oneeighth of the concentration of unsubstituted salicylanilidewhich is required by itself to prevent growth, is also incorporated in amixture of the four derivatives, growthinhibiting activity can beachieved with even smaller concentrations of the derivatives, i. e. inthe last-mentioned combination.

In addition to the important advantage demonstrated above, namely thatin the present invention low concentrations of chloro-derivatives can begenerally used for preventing the growth of mold organisms against whichsuch derivatives could not heretofore be employed, there are furtheradvantages of a specific character to be realized. Thus it is found thatthe new antifungal compositions also show improved activity againstthose organisms toward which the individual compounds of the statedclass could be shown to have growth inhibiting activity by themselves.Under such circumstances, the new compositions can be employed withgreater safety or less likelihood of irritation or other undesirableresults; indeed against any of a wide variety of organisms, thecompositions may be effective with a total concentration of activeagents which is so slow as to be harmless to living tissue. It will beunderstood that other advantages, including economy of the activeagents, similarly flow from the improved activity which the combinationexhibits against various organisms. These results are further and isitselfsensitive to the individual chlorosalicylanilides, by

and the PH being 6.2.

specifically shown, e. g. in relation to an organism which TABLE IIAmounts used (mg. per I cc.) of Salicylkznilid'e derivative 4'- 5,2'-5,2 4'- i" dichloro. dichloro tricbloro Results No growth. Growth. N0growth. Growth. No growth. Growth. No growth. Growth. 0.0 Nogrowt-h,0.02 0.0013 0.0013 Growth.

It will be seen at once that a condition of growth inhibit io'n wasachieved with the combination or four substances, at concentrations ofeach which are much below the concentration required separately of eachfor preventing organism growth; Furthermore, the total concentration (inthis particular series of experiments) needed to inhibit growth with thecombination was only 0.03 milligram per 100 cc. of the medium, whereasin the case of S-chldrosalicylanilide alone, growth was still evident inthe presence of 0.04 milligram and could only be inhibited by a stilllarger concentration, i. e. 0.08 milligram.

Another advantage of the compositions of the invention is that moreeffective, actual concentrations can be reached in materials such asleather, fabrics, live skin, hair, mucous membranes, fruits, plants andsimilar possible sites of fungus contamination, such improved resultsbeing attainable by the simultaneous and independent diffusion orpenetration of the individual agents (which compose the composition)into the various materials described. A still further feature of notableutility in the compositions is that they possess powerfulantibacterialproperties, a valuable attribute in therapeutic or like application ofthe composition, such properties thus being exhibited along with thedescribed universality of antifungal action, which in itself has notheretofore been attained with these chloroderivatives of salicylanilide.

. As indicated above, the several compounds of the stated class, with orwithout the unsubstituted salicylanilide, may be employed in any one ofmany combinations. For instance in the set of experiments reported inthe followingftable, various combinations of four substances selectedfrom a group of five were tested, in comparison with attempts to inhibitgrowth by using each of the substances alone. The test organism in theseexperiments was Saccharomyces cerevisiae, the medium being Sabouraudsbroth containing 0.5% ethanol, at a pH of 7.2.

TABLE III Amounts used, in mg. per 100 cc.

diehloro dichloro dichloto Results Growth. No Growth. Growth.

Do. No Growth Growth. No Growth. Trace. No Growth. 'lrace.*

No Growth.

Trace." No Growth. Trace.*

Iii-most cases no concentration of the individual compounds Could berachd which WO'uldihhibit glowth of the organisms,-the sole exceptionbeing in the case of'the 5,4J-dichloro' derivative, where inhibition wasachieved at a concentration of 2 milligrams per cc., this result beingapparently due to the higher pH, as explained above. It will be apparentfrom Table III that various combinations of the agents were found to beeffective, the results (marked. with an asterisk) which represent atrace of growth being referred to the final reading after hours. In theinstances last mentioned, no growth was observed after only 48 hours.Hence it may be taken that in each of the combinations of 4 substances,completely effective results might be had with only slightly higherconcentrations than specifically stated to have resulted in a trace ofgrowth. It will also be noted that by a combination of two derivatives,the 5-chloro and 5,4',2- trichloro compounds, growth was inhibitedwhereas neither of: these substances alone could be shown to have anyactivity against the. test organism. It may also be noted from acomparison of Tables I and III, that the improved results are attainableindependently of the hydrogen ion concentration of the medium.

While the relative amounts of the individual compounds embodied in thenew compositions may vary considerably, it appears that in certaincases, especially where the composition contains only two or threecompounds (of the stated class consisting of salicylanilide andchlorosalicylanilides), the advantages of combination are poorlyrealized if the ingredient or ingredients having greater intrinsicactivity and being usually less soluble are present in substantiallylarger quantities than the less active and more soluble ingredient oringredients. Indeed it is generally important, according to presentunderstanding, that the selected substances be associated in at leastequal amounts orif not, then in approximately inverse proportion totheir intrinsic activity. That is to say, the activity (or at least, theintrinsic activity) may be deemed to increase with increase in thenumber or order of chlorine atoms, unsubstituted salicylanilide beingconsidered as of zero, i. e. lowest order of chlorine content. Thus theun usually useful compositions are those wherein the total quantity ofthe compound (or of the compounds) of each lower order (i. e. each orderlower than the highest present) is not appreciably less than (or inother words, is at least about as great as) the amount present of anyone compound of a higher order.

Hence if the composition consists of salicylanilide and a singlechlorsalicylanilide (of any order), the amount of the unsubstitutedcompound should be at least as. great as, or greater than, the amount ofthe chloro derivative. Likewise, for instance, if the compositioncomprises a monochloro salicylanilide and a chloro derivative of higherorder (having two or more chlorine atoms), the amount of the monochloroderivative should be at least as large as that of the higher orderderivative. In similar fashion, if the combination selected from thebasic class consists of three or more compounds of different order theamount of the compound of lowest order should preferably be as much as,or more than, that of the chloro derivative of intermediate order, andthe quantity of the latter should in turn be as much as, or more than,that of the higher order derivative. I

It is at present understood that these relationships of proportion amongthe several orders of compound are primarily requisite when thecomposition contains only two substances of the class, or not more 'thanthree substances, in the latter case particularly if one of the three isthe unsubstituted salicylanilide and the other two are of V mutuallydifferent orders of chlorine content; although it may sometimes bedisregarded (e. g. when three or more chloro derivatives are present),the relationship is nevertheless preferred and advantages in all cases,namely to have the total amount of compound material present of eachlower order (there being ten possible orders' of chlorine content, fromzero to nine) at least as 5 great as the amount present of any oneindividual compound of a higher order. A further example of a composition coming within this rule of proportionality is one that embodiesone part of salicylanilide, one part of trichlorosalicylanlide, twoparts of another trichlorosalicylanilide, and three parts of atetrachlorosalicylanilide.

The following are additional examples of particularly usefulpreparations according to the invention. One such compositon containsfour parts of salicylanilide,

I two parts of a monochlorosalicylanilide and one part .of thesecompounds are at present preferred for inclusion in the compositions, e.g., by reason of availability, economy and greater solubility. Forinstance, an unusually satisfactory composition, in all of theserespects and likewise in respect to effectiveness of antifungal action,is one wherein one of the plurality of compounds from the stated classis S-chlorosalicylanilide. Ingredients also presently found to be ofspecial preference, for one or more of the same reasons, are5,4-dichlorosalicylanilide, 5,3-dichlorosalicylanilide, and5,2,4-trichlorosalicylanilide.

The salicylanilide derivatives which are employed in the compositionsherein described can be prepared by various methods, e. g., procedureswhich will be well known. to, or readily understood by, those skilled inthe art; hence it is believed necessary only to mention such proceduresbriefly, in the case of certain compounds as examples, with theunderstanding that corresponding operations, or other methods whichmaybe known or readily adopted in the art, may be employed in the caseof other specific chloro derivatives as may be desired.

Thus, for example, 5,3-dichlorosalicylanilide can be prepared by heatingS-chlorosalol with 3-chloroaniline to l80220 C. and continuouslydistilling the liberated phenol off during this process. It isadvantageous to use reduced pressure for this distillation and to carryout the procedure in a nitrogen atmosphere. The crude reaction productis dissolved in alcohol to which an equivalent amount of sodiumhydroxide is added in the form of approximately l0-n aqueous solution.The resulting solution of the sodium salt of 5,3'-dichlorosalicylanilideis then decolorized with charcoal and neutralized with dilutehydrochloric acid. The 5,3'-di'chlorosalicylanilide thus precipitated isfiltered and recrystallized from ethyl alcohol, ethyl acetate, or someother suitable solvent.

As indicated, still other methods can be employed for preparation ofthese chloro derivatives. For instance, instead of the phenolic ester ofS-chlorosalicylic acid (i. e., identified above by its common name,S-chlorosalol) other esters of S-chlorosalicylic acid may be used, suchas the ethyl ester or the methyl ester. The chlorosalicylanilides canalso be prepared in some instances by heating the salicylic acid and theaniline (one or both of which is substituted with one or more chlorineatoms) in the presence of small amounts of phosphorus pentachloride anda tertiary organic base such as dimethylaniline.

As explained, the essential active part or basis of the new compositionsis the combination of a plurality of 7 compounds selected from thestated class. In all cases, it

is assumed that each of the selected active ingredients of thecombination will be present in an effective amount, for example inamount equal to or greater than at least. 10% of the amount of that oneof the compounds which is present in next larger quantity, thedefinition of the-composition herein being understood as disregardingminor or trace amounts of other members of the stated class which mayhappen to be present, for example'because 8 necessarily occurring as animpurity or impurities, so to speak ,.in the original production of oneor another-of the compounds selected as primary ingredients.

It will be understood that in most cases the composition also actuallyincludes a suitable carrier in uniform admixture with the activeingredients, e. g. appropriately distributing the ingredients whilemaintaining their mutually eifective'icombination with each other, andfacilitating application of the active combination to the surface orother locality of use, e. g. for such spreading, penetration or otherspecial access as maybe required of the active ingredients for theantifungal effect. Thus for therapeutic use, e. g. to prevent or totreat fungus infection, the combination with the carrier may be such asto provide a powder, liquid (i. e. lotion) or ointment, e. g. aspreadable preparation in which the active combination of ingredients isuniformly and smoothly distributed, preferably in stable suspension orsolution. In therapeutic uses, the

total amount of combination here described (i. e. the effectivecombination of substances from the stated class) may ordinarily rangefrom 0.1% to 30% of the complete composition, at least a major part (andoften all) of the remainder of the composition being' usually an inertcarrier material, which may itself comprise or include water in the caseof lotions and ointments. In making up compositions with a suitablecarrier, it will be understood that the individual compounds may beadded or adsorbed to the carrier powder, or can be suspended ordissolved in a liquid or ointment.

In exceptional cases, larger proportions of the combination ofsalicylanilide compounds may be employed, there being utility in certaincircumstances even for a preparation which consists wholly of the activeingredients, e. g. two or more compounds from the class ofsalicylanilide and chlorosalicylanilides. For antifungal purposes innon-therapeutic circumstances, as to prevent mold growth on fabrics,leather, and various other materials, it will be understood that powdersor preferably solutions may be used, with or without additional carriermaterial, i. e. other'than water in the case of solutions.

The composition can also advantageously be combined with fatty acids ortheir salts, especially substances having pronounced antifungalproperties, some examples being propionic acid, caprylic acid, andlikewise the unsaturated acids containing from 6 to 12 carbon atoms,notably undecylenic acid, as well as salts of these acids, such assodium propionate and particularly zinc undecylenate. Other substancesthat may be included in the combination are anionic wetting agents. Bothof these additives, i. e. fatty acids (or salts) and anionic wettingagents, have been found to enhance the activity of the preparation inpractice. Whereas the anionic wetting agents are thus found beneficial,present experience has indicated that the non-ionic wetting agents,although they may be of utility as good solubilizing agents for thesecompounds (e. g. the chlorosalicylanilides), tend to decrease theeffectiveness of the composition.

The following are a number of specific examples of preparations whichare of special value in practical application under variouscircumstances as indicated. It will be understood, nevertheless, thatthese are simply set forth by way of example and that a variety of othercombinations may be prepared, including various different combinationsof the active ingredients and likewise a variety of carrier and othersupplemental materials. In all cases, and indeed elsewhere in thisspecification, reference to parts or percentages are intended to meanvalues by weight, unless otherwise specifically indicated.

Example I An effective antimycotic ointment, adapted for. treatment offungous infections, e. g. for topical application to treat suchinfections of the skin, is made according to the following formula:

Parts S-chlbrbsalicylanilide ;1 t s;a1 c--.. s 0.55,2-dichlorosalicylanilide -1; 0.5 5,4'-dichlorosalicylanilide 0.25,3-dichlorosalicylanilide 0.2 5,2,4'-trichlorosalicylanilide 0.2Polyethylene glycol base N. F 93.0

Example II A dusting powder, particularly advantageous in the preventionand treatment of fungous infections,- is prepared in the followingmanner: h

Two pounds each of 5-chloro, 5,4'-dicliloro, and 5,3-dichlorosalicylanilides are dissolved in a sufficient amount 'of ethylacetate to give a clear solution and to cover 200 pounds of talc whichare added to the stated solution. The alcohol is then evaporated undercontinuous stirring and the powder dried. It now contains 1% of each ofthe salicylanilide derivatives and it is useful in the treatment andprevention of fungous infections.

Example III This is a liquid preparation which is of special value intreating fungous infections of the external auditory canal, and whichmay therefore be employed as ear drops, for such treatment:

Parts S-chlorosalicylanilide 0.5

5,3'-dichlorosalicylanilide 0.5

5,4'-dichlorosalicylanilide 0.5

Polyethylene glycol (400) 63.5

Glycerine 35.0 Example IV Another antimycotic preparation, in the formof a solution which is useful in the treatment of skin infections causedby fungi, has the following formula. Although this composition (likeother examples, below) also includes a certain amount of anotherantifungal agent, e. g. undecylenic acid, the advantages of theinvention respecting the combination of salicylanilide and twochlorosalicylanilides are abundantly realized, i. e. in obtainingactivity, with an unusually small amount of active material, againstorganisms toward which each of the chloro compounds is notsatisfactorily effective alone.

Parts 5,4'-dichlorosalicylanilide 0.5 5-chlorosalicylanilide 1.0Salicylanilide 2.0 Undecylenic acid 2.0 'Iriethanolamine 0.5 n-Propanol30.0 Acetone 30.0 Polyethylene glycol (300) 24.0 Sodium lauryl sulfate.1 Distilled water ad 100.0

Example V This preparation is of considerable utility as a scalp lotion,i. e. for treating fungous disorders of the scalp:

ExampleVI The following is an antirnycotic cream suitable for variouspurposes, for instance in the treatment of mucous @erhbranes infected byfungi, especially the species known as Monilia albicans:

Example VII Many other uses, as for antifung'al action on leather,fabrics, fruits, plants and other sites of undesirable mold growth, arecontemplated for the described novel combinations of a plurality ofsubstances selected from the class consisting of salicylanilide and thechlorosalicylanilides. For instance, one composition which thus embodiesthe invention and which may be employed for the moldproofing of fabrics,is prepared as follows:

A solution of the sodium salts of each of the following salicylanilidecompounds: 5,2- and 5,3-dichloro-, and 5,2,4-trichlorosalicylanilide, isprepared by dissolving one pound of each of these three compounds inlbs. of an alcoholic sodium hydroxide solution containing gms. of sodiumhydroxide, the liquid components of the solution being ethyl alcohol 30%and water 70%, but aqueous solutions of the sodium salts can also beused. This solution can be applied to a fabric in various ways, aconvenient procedure being simply to pass the fabric through thesolution. The fabric is then wrung or squeezed almost dry, and finallydried by evaporation. A deposit of the intimately mixed compoundsremains in or upon the fibers, and is effective, over a long period oftime, to prevent mold or mildew on the fabric. A similar solution, to beused in the same way and with like effect, can be made by dissolving thesodium salts of the salicylanilide derivatives in ethyl alcohol, e. g.commercial 95% ethanol.

Although it is preferred to use compositions which contain one or morechlorinated salicylanilides, and although the invention is in aprincipal or specific sense directed to the chlorosalicylanilides,results similar to those described throughout the foregoingspecification can be obtained with derivatives of salicylanilide ofwhich one or more hydrogens in the aromatic rings are replaced by ahalogen of higher atomic weight than chlorine, such asS-bromosalicylanilide, 5-iodosalicylanilide, 5,4'-dibromosalicylanilide,5,3-dibromosalicylanilide, and the corresponding di-iodosalicylanilides,and salicylanilides in which one or more hydrogen atoms of the aromaticring of the salicyl moiety is replaced by a heavier halogen thanchlorine, whereas one or more hydrogen atoms of the aromatic ring of theaniline moiety are replaced by chlorine and vice versa. These compoundsmay be defined as halogen derivatives of salicylanilide, the halogenbeing of greater atomic Weight than fluorine.

It is to be understood that the invention is not limited to the specificcompositions herein described by way of example, but may be embodied inother forms without departure from its spirit.

I claim:

1. An antifungal composition comprising as active ingredientssalicylanilide and at least three chlorosalicylanilides, each of whichcontains less than five chlorine atoms.

2. An antifungal composition comprising as active ingredientssalicylanilide and at least two chlorosalicylanilides each of whichcontains less than five chlorine atoms.

3. An antifungal composition as defined in claim 2 in which the twochlorosalicylanilides are respectively S-chlorosalicylanilid and5,4-dichlorosalicylanilide.

4. An. antifungal composition comprising as active ingredients:5,3-dichlorosalicylanilide, 5,4-dichlorosalicylanilide;S-chlorosalicylanilide in amount at least as great as the amount of oneof said first and secondmentioned 'chlorosalicylanilides; andsalicylanilide in amount at least as great as the amount of saidS-chlorosalicylanilide.

5. An antifungal' composition comprising as active ingredients at leastthree different compounds selected from the class consisting ofsalicylanilide and halogen derivatives of salicylanilide that containless than five halogen atoms, the halogen atoms of said derivativesbeing of greater atomic weight than fluorine, and the entire halogencontent in each derivative being of a single haolgen element.

6. An antifungal composition comprising as active ingredientssalicylanilide and at least two halogen derivatives of salicylanilidethat contain less than five halogen atoms, the halogen atoms ofsaidrderivatives being of greater atomic weight than fluorine, and theentire halogen content in each derivative being of a single halogenelement. H i t v References Cited in the file of this patent UNITEDSTATES PATENTS Fargher Aug. 23, 1932 Wyman Dec. 4, 1951 OTHER REFERENCES0 1953, page 1430.

5. AN ANTIFUNGAL COMPOSITION COMPRISING AS ACTIVE INGREDIENTS AT LEASTTHREE DIFFERENT COMPOUNDS SELECTED FROM THE CLASS CONSISTING OFSALICYLANILIDE AND HALOGEN DERIVATIVES OF SALICYLANILIDE THAT CONTAINLESS THAN FIVE HALOGOEN ATOMS, THE HALOGEN ATOMS OF SAID DERIVATIVESBEING OF GREATER ATOMIC WEIGHT THAN FLUORINE, AND THE ENTIRE HALOGENCONTENT IN EACH DERIVATIVE BEING OF A SINGLE HAOLGEN ELEMENT.